Mental disorders with complex traits such as schizophrenia pose a difficult challenge in the identification of etiological factors. Evidence from genetic epidemiological studies indicate that schizophrenia and allied mental disorders are the result of an interaction between genetic factors and early environmental insults that disrupts neurodevelopmental processes and lead to latent manifestation of disease. It has been estimated that in the United States alone, over 25% of adults are diagnosed with at least one mental disorder and this carries an enormous social and economic burden. Disrupted-in-Schizophrenia 1 (DISC1) is a gene that was originally identified at the breakpoint of a balanced (1;11) translocation that co- segregates with schizophrenia and mood disorders in a large Scottish family. Independent evidence for the involvement of DISC1 in psychiatric disorders has now been confirmed in other populations. Studies in animal models expressing the human mutant form of DISC1 indicate that it has an important role in neurodevelopment, neuronal signaling and cognition. Expression of the human mutant DISC1 protein in mice shows a number of behavioral abnormalities that are similar to those in schizophrenia subjects. Other evidence indicates that DISC1 regulates development of adult born granule cell neurons and axonal and dendritic development in the hippocampus. While environmental factors have been implicated in mental disorders, no previous study has examined the role of a specific environmental pollutant in mental disease. In this proposal, we seek to characterize a new animal model of gene-environment interaction relevant to the etiology and pathogenesis of schizophrenia and allied mental disorders. We have selected developmental lead (Pb2+) exposure as the environmental trigger because previous studies from this laboratory have shown that Pb2+ is a potent NMDA receptor antagonist and developmental Pb2+ exposure produces behavioral and neurobiological changes with overlapping features to those in transgenic mice expressing the human mutant DISC1 protein. The proposed studies will use behavioral, neurobiological and state-of-the-art neuroimaging methods to assess the effects of developmental Pb2+ exposure in mice expressing the mutant human DISC1 protein to provide an innovative platform for studying this complex disease. We anticipate that the results of the proposed studies will advance our understanding of the mechanisms of gene-environment interaction pertinent to the pathogenesis of schizophrenia and related mental disorders.